rs1052555

chr19-45352266-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000400.4(ERCC2):c.2133C>T(p.Asp711=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,738 control chromosomes in the GnomAD database, including 80,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6022 hom., cov: 32)
  • Exomes 𝑓: 0.31 (74695 hom.)
• Consequence: ERCC2 NM_000400.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.818

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-45352266-G-A is Benign according to our data. Variant chr19-45352266-G-A is described in ClinVar as [Benign]. Clinvar id is 256018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45352266-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.818 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4	c.2133C>T	p.Asp711=	synonymous_variant	22/23	ENST00000391945.10
ERCC2	XM_011526611.3	c.2055C>T	p.Asp685=	synonymous_variant	21/22
ERCC2	XR_001753633.3	n.2166C>T		non_coding_transcript_exon_variant	22/24
ERCC2	XR_007066680.1	n.2088C>T		non_coding_transcript_exon_variant	21/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10	c.2133C>T	p.Asp711=	synonymous_variant	22/23	1	NM_000400.4	P1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38856 AN: 152004 Hom.: 6024 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.0612

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.266

GnomAD3 exomes AF: 0.282 AC: 70750 AN: 251206 Hom.: 11570 AF XY: 0.295 AC XY: 40066 AN XY: 135792

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.0651

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.312 AC: 455390 AN: 1461616 Hom.: 74695 Cov.: 47 AF XY: 0.314 AC XY: 228392 AN XY: 727104

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.0433

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.298

GnomAD4 genome AF: 0.255 AC: 38849 AN: 152122 Hom.: 6022 Cov.: 32 AF XY: 0.257 AC XY: 19127 AN XY: 74360

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.360

Gnomad4 EAS AF: 0.0607

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.262

Alfa AF: 0.301 Hom.: 6431

Bravo AF: 0.230

Asia WGS AF: 0.160 AC: 561 AN: 3478

EpiCase AF: 0.344

EpiControl AF: 0.344

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with reduced cancer risk -

Xeroderma pigmentosum, group D Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	This variant is associated with the following publications: (PMID: 15834925) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Cerebrooculofacioskeletal syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Trichothiodystrophy 1, photosensitive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.34
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1052555; hg19: chr19-45855524; COSMIC: COSV67266435; COSMIC: COSV67266435;